Loss of Foxd3 Results in Decreased β-Cell Proliferation and Glucose Intolerance During Pregnancy

Abstract

A complete molecular understanding of ␤-cell mass expansion will be useful for the improvement of therapies to treat diabetic patients. During normal periods of metabolic challenges, such as pregnancy, ␤-cells proliferate, or self-renew, to meet the new physiological demands. The transcription factor Forkhead box D3 (Foxd3) is required for maintenance and self-renewal of several diverse progenitor cell lineages, and Foxd3 is expressed in the pancreatic primordium beginning at 10.5 d postcoitum, becoming localized predominantly to ␤-cells after birth. Here, we show that mice carrying a pancreas-specific deletion of Foxd3 have impaired glucose tolerance, decreased ␤-cell mass, decreased ␤-cell proliferation, and decreased ␤-cell size during pregnancy. In addition, several genes known to regulate proliferation, Foxm1, Skp2, Ezh2, Akt2, and Cdkn1a, are misregulated in islets isolated from these Foxd3 mutant mice. Together, these data place A pproximately 7% of pregnant women are affected by gestational diabetes mellitus (GDM), a disease resulting from the inability of the resident ␤-cell population to produce sufficient insulin during pregnancy (1). GDM increases the risk of complications to both mother and newborn child; the mother is more likely to develop type 2 diabetes later in life, and the child is more likely to be born with birth defects, macrosomia, and an increased risk of developing type 2 diabetes (2-6). During normal murine pregnancy, ␤-cells proliferate, or self-renew, thereby expanding the total ␤-cell mass to meet the mother's increasing demand for insulin (1,(7)(8)(9)(10)(11)(12). This mechanism of ␤-cell mass expansion during human pregnancy remains controversial. Analogous measurements are not ethically feasible in humans. However, morphological analyses of human pancreata indicate that ␤-cell mass is increased during pregnancy (13,14). Recent work analyzing pancreata from 38 cadaveric donors (18 pregnant, 20 controls) suggested that ␤-cells do not proliferate during human pregnancy. Instead, an increased number of smaller islets and insulin-positive cells was observed within the ductal epithelium (15). However, this work is not without caveats. It is well known that murine ␤-cells proliferate within a defined time window, and it is likely that the 18 pregnant human donors examined were not within an analogous gestational age (16,17). This study also included donors with inflammatory disease that may have adversely affected ␤-cell mass expansion (18). It is important to note that the pregnancy-associated hormones prolactin, placental lactogen (PL), and human growth hormone all stimulate ␤-cell proliferation in islets isolated from mice, rats, and humans, suggesting that cell proliferation is a conserved mechanism of Abbreviations: BrdU, 5-Bromo-2-deoxyuridine; Cdkn, cyclin-dependent kinase inhibitor; ES, embryonic stem; Ezh2, enhancer of zeste homolog 2; Foxa2, Forkhead box A2; Foxd3, Forkhead box D3; Foxm1, forkhead box M1; GDM, gestational diabetes mellitus; IPGTT, ip glucose tolerance testing;...

Substrate-mediated reprogramming of human fibroblasts into neural crest stem-like cells and their applications in neural repair

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Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and β-Cell Function

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High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice

“…Subsequent changes in blood glucose were measured at 15-, 30-, 60-, 90-, and 120-min intervals following injection; n ϭ 3 (weeks 3, 7, and 9) or 6 (weeks 1, 5, and 11). Plasma insulin assays were performed as described in (31), with the modification that blood was harvested from the saphenous veins of 16-h-fasted animals using heparinized Natelson bloodcollecting tubes (Kimble Chase, Rockwood, TN).…”